scholarly journals Facing COVID-19 via anti-inflammatory mechanism of action: Molecular docking and Pharmacokinetic studies of six anti-inflammatory compounds derived from Passiflora edulis

2020 ◽  
Author(s):  
Aristote Matondo ◽  
Jason T Kilembe ◽  
Domaine T Mwanangombo ◽  
Beaudrique M Nsimba ◽  
Benjamin Z Gbolo ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Pharmacokinetic Studies ◽  
Potential Treatment ◽  
Cytokine Storm ◽  
Passiflora Edulis ◽  
Main Protease ◽  
Inflammatory Mechanism ◽  
Pharmacokinetic Properties ◽  
Docking Calculations ◽  
Anti Inflammatory

Abstract SARS-CoV-2 is the causative agent of the COVID-19 disease. Pathophysiologically, high levels of proinflammatory cytokines in the serum of SARS-CoV-2 patients are reported, which is so-called the cytokine storm. In this study, molecular docking calculations of six bioactive compounds from Passiflora edulis with anti-inflammatory activity in interaction with the main protease of SARS-CoV-2 were performed, and their pharmacokinetic properties were predicted. The results of their molecular simulations and the ADME-T profiles of each ligand (Absorption, Distribution, Metabolism, Excretion and Toxicity) suggest their use as potential treatment for SARS-CoV-2. Among the six investigated compounds in which four flavonoids and two alkaloids, the best docked ligands are quercetin (-8.2 kcal/mol), chrysin (-8.0 kcal/mol), kaempferol (-7.9 kcal/mol) and luteolin (-7.7 kcal/mol), both flavonoids compounds. Their pharmacokinetic studies using SwissADME, preADMET and pkCSM Web servers establish the good ADMET profile for each ligand.

scholarly journals Facing COVID-19 Via Anti-Inflammatory Mechanism of Action: Molecular Docking and Pharmacokinetic Studies of Six Anti-Inflammatory Compounds Derived from Passiflora edulis

2021 ◽  
pp. 35-51
Author(s):  
Aristote Matondo ◽  
Jason T. Kilembe ◽  
Domaine T. Mwanangombo ◽  
Beaudrique M. Nsimba ◽  
Dani T. Mawete ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Severe Case ◽  
Binding Energies ◽  
Inflammatory Activity ◽  
Pharmacokinetic Studies ◽  
Passiflora Edulis ◽  
Potential Inhibitor ◽  
Main Protease ◽  
Anti Inflammatory ◽  
Pharmacokinetic Behavior

Aim: In the most severe case of the COVID-19, there is an excessive production of proinflammatory cytokines, being the main cause of mortality and morbidity. The present study aims at assessing the potential inhibitor effect of six phytochemicals with anti-inflammatory activity derived from Passiflora edulis, against the SARS-CoV-2 main protease. Materials and Methods: Virtual screening by molecular docking (Autodock tool) was used to obtain the binding energies of ligand-protein complexes formed between each of the six ligands and the SARS-CoV-2 main protease. The six ligands were then submitted to ADME (absorption, distribution, metabolism and excretion) and toxicity analyses to understand their pharmacokinetic behavior, using SwissADME, preADMET and pkCSM webservers. Results: Four high-docking score compounds were identified (both flavonoids) as hits, with the trend: ligand 4 (quercetin, -8.2 kcal/mol ) > ligand 1 (chrysin, -8.0 kcal/mol) > ligand 2 (kaempferol, -7.9 kcal/mol) > ligand 3 (luteolin, -7.7 kcal/mol)> ligand 5 (harmol, -6.7 kcal/mol) > ligand 6 (harmine, -6.4 kcal/mol). The pharmacokinetic behavior of the six ligands revealed that they can be easily absorbed and have good permeability and bioavailability. The toxicity predictions of the six compounds from P. edulis which is an editable fruit confirm that they are safe. Conclusion: Several approaches are currently being used to tackle the COVID-19. Given the cytokine storm in the most severe case of the COVID-19, we adopted the strategy of combatting the disease by compounds that exhibit anti-inflammatory activity. The assessment of the efficiency of six phytochemicals from P. edulis against the SARS-CoV-2 Mpro and their pharmacokinetic profile revealed their potential inhibitor effect against the COVID-19 protein.

scholarly journals Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 653
Author(s):  
Seth O. Asiedu ◽  
Samuel K. Kwofie ◽  
Emmanuel Broni ◽  
Michael D. Wilson
Keyword(s):  
Molecular Docking ◽  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Binding Energies ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Activity ◽  
Computational Techniques ◽  
Cytokine Storm ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

scholarly journals A Dispersion Corrected DFT Investigation of the Inclusion Complexation of Dexamethasone with β-Cyclodextrin and Molecular Docking Study of Its Potential Activity against COVID-19

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7622
Author(s):  
Youghourta Belhocine ◽  
Seyfeddine Rahali ◽  
Hamza Allal ◽  
Ibtissem Meriem Assaba ◽  
Monira Galal Ghoniem ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Active Sites ◽  
Density Functional ◽  
Inclusion Complexation ◽  
Docking Study ◽  
Van Der Waals Interactions ◽  
Molecular Docking Study ◽  
Main Protease ◽  
Docking Calculations ◽  
Potential Activity

The encapsulation mode of dexamethasone (Dex) into the cavity of β-cyclodextrin (β-CD), as well as its potential as an inhibitor of the COVID-19 main protease, were investigated using density functional theory with the recent dispersion corrections D4 and molecular docking calculations. Independent gradient model and natural bond orbital approaches allowed for the characterization of the host–guest interactions in the studied systems. Structural and energetic computation results revealed that hydrogen bonds and van der Waals interactions played significant roles in the stabilization of the formed Dex@β-CD complex. The complexation energy significantly decreased from −179.50 kJ/mol in the gas phase to −74.14 kJ/mol in the aqueous phase. A molecular docking study was performed to investigate the inhibitory activity of dexamethasone against the COVID-19 target protein (PDB ID: 6LU7). The dexamethasone showed potential therapeutic activity as a SARS CoV-2 main protease inhibitor due to its strong binding to the active sites of the protein target, with predicted free energy of binding values of −29.97 and −32.19 kJ/mol as calculated from AutoDock4 and AutoDock Vina, respectively. This study was intended to explore the potential use of the Dex@β-CD complex in drug delivery to enhance dexamethasone dissolution, thus improving its bioavailability and reducing its side effects.

scholarly journals Some Compounds from Neem leaves extract exhibit binding affinity as high as -14.3 kcal/mol against COVID-19 Main Protease (Mpro): A Molecular Docking Study

2020 ◽  
Author(s):  
Shanmuga Subramanian S
Keyword(s):  
Molecular Docking ◽  
Treatment Option ◽  
Vitamin B1 ◽  
Antiviral Agent ◽  
Docking Study ◽  
Binding Energies ◽  
Potential Treatment ◽  
Molecular Docking Study ◽  
Main Protease ◽  
Neem Leaves

Abstract Currently the new Coronavirus "COVID-19", also known as SARS-CoV-2, has infected nearly 3 million patients and nearly 200,000+ people have lost their lives due to this pandemic. There is an urgent need to find an antiviral agent that may slow down the spread of the virus. The aim of this study is to assess and evaluate compounds present in leaves of Neem tree (Azadirachta Indica) as potential inhibitors for COVID-19 Main Protease (Mpro) (PDB code: 6LU7). This will be done by blind molecular docking using PyRx and Auto Vina software. The compounds Hydroxychloroquine and Remdesivir were used for comparative study. The binding energies obtained from the docking of 6LU7 with meliacinanhydride, nimocinol, isomeldenin, nimbolide, zafaral, nimbandiol, nimbin, nimbinene, desacetylnimbin were -14.3, -12.4, -12.3, -12.2, -11.9, -11.8, -11.7, -11.7, -11.4 kcal/mol respectively. Therefore Meliacinanhydride (Ki=33.36 pM) and the compounds from Neem leaves may be a potential treatment option against COVID-19. In addition to that the leaves contain others compounds like Quercetin, Zinc,Vitamin A,Vitamin B1,B2,B6, Vitamin C,Vitamin E etc., which may boost immunity also (Garba, 2019) .Further investigation is needed to evaluate the results of this study to consider Neem leaves as potential treatment option as it might inhibit the virus and boost immunity also

scholarly journals Molecular Docking and Fragment-Based QSAR Modeling for In Silico Screening of Approved Drugs and Candidate Compounds Against COVID-19

2020 ◽  
Vol 8 (2) ◽  
pp. 83-88
Author(s):  
Saeid Afshar ◽  
Asrin Bahmani ◽  
Massoud Saidijam
Keyword(s):  
Molecular Docking ◽  
Autodock Vina ◽  
Qsar Modeling ◽  
Health Crisis ◽  
Mortality And Morbidity ◽  
Main Protease ◽  
Docking Calculations ◽  
Approved Drugs ◽  
Top 40 ◽  
Potential Inhibitors

Background: Coronavirus disease 2019 (COVID-19) as a serious global health crisis leads to high mortality and morbidity. However, currently, there are no effective vaccines and treatments for COVID-19. Main protease (Mpro) and angiotensin-converting enzyme 2 (ACE2) are the best therapeutic targets of COVID-19. Objectives: The main purpose of this study is to investigate the most appropriate drug and candidate compound for proper interaction with Mpro and ACE2 to inhibit the activity of COVID-19. Methods: In this study, repurposing of approved drugs and screening of candidate compounds using molecular docking and fragment-based QSAR method were performed to discover the potential inhibitors of Mpro and ACE2. QSAR and docking calculations were performed based on the prediction of the inhibitory activities of 5-hydroxy indanone derivatives. Based on the results, an optimal structure was proposed to inhibit the activity of COVID-19. Results: Among 2629 DrugBank approved drugs, 118 were selected considering the LibDock score and absolute energy for possible drug-Mpro interactions. Furthermore, the top 40 drugs were selected based on screening the results for possible drug- Mpro interactions with AutoDock Vina. Conclusion: Finally, evaluation of the top 40 selected drugs for possible drug-ACE2 interactions with AutoDock Vina indicated that deslanoside (DB01078) can interact effectively with both Mpro and ACE2. However, prior to conducting clinical trials, further experimental validation is needed.

scholarly journals Assessing the Anti-inflammatory Mechanism of Reduning Injection by Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Fuda Xie ◽  
Mingxiang Xie ◽  
Yibing Yang ◽  
Miaomiao Zhang ◽  
Xiaojie Xu ◽  
...  
Keyword(s):  
Data Mining ◽  
Molecular Docking ◽  
Signaling Pathway ◽  
Complex Disease ◽  
Inflammatory Diseases ◽  
Estrogen Signaling ◽  
Network Pharmacology ◽  
Inflammatory Mechanism ◽  
Reduning Injection ◽  
Anti Inflammatory

Reduning Injection (RDNI) is a traditional Chinese medicine formula indicated for the treatment of inflammatory diseases. However, the molecular mechanism of RDNI is unclear. The information of RDNI ingredients was collected from previous studies. Targets of them were obtained by data mining and molecular docking. The information of targets and related pathways was collected in UniProt and KEGG. Networks were constructed and analyzed by Cytoscape to identify key compounds, targets, and pathways. Data mining and molecular docking identified 11 compounds, 84 targets, and 201 pathways that are related to the anti-inflammatory activity of RDNI. Network analysis identified two key compounds (caffeic acid and ferulic acid), five key targets (Bcl-2, eNOS, PTGS2, PPARA, and MMPs), and four key pathways (estrogen signaling pathway, PI3K-AKT signaling pathway, cGMP-PKG signaling pathway, and calcium signaling pathway) which would play critical roles in the treatment of inflammatory diseases by RDNI. The cross-talks among pathways provided a deeper understanding of anti-inflammatory effect of RDNI. RDNI is capable of regulating multiple biological processes and treating inflammation at a systems level. Network pharmacology is a practical approach to explore the therapeutic mechanism of TCM for complex disease.

scholarly journals Based on Proteomics Reveals the Anti-inflammatory Mechanism of Phillygenin by Inhibition NF-κB Pathway

2020 ◽  
Author(s):  
Mengting Zhou ◽  
Yunqiu Tang ◽  
Li Liao ◽  
Meichen Liu ◽  
Ying Deng ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Western Blot ◽  
Signaling Pathways ◽  
Inflammatory Factors ◽  
Transcriptional Level ◽  
Inflammatory Genes ◽  
Inflammatory Mechanism ◽  
Pathway Activation ◽  
Anti Inflammatory ◽  
Anti Inflammation

Abstract Background: Inflammation is a common pathological phenomenon when homeostasis is seriously disturbed. Phillygenin (PHI) is a lignin component isolated from Forsythiae Fructus, which showed a good anti-inflammation effect. However, the mechanisms of PHI on anti-inflammation have not yet been systematically elucidated.Methods: In the study, the lipopolysaccharide (LPS)-induced RAW264.7 cell inflammation model was established to investigate mechanisms of PHI on inflammation. The effect of PHI on LPS-induced IL-1β and PGE2 inflammatory factors was detected by ELISA, and the mRNA expression of IL-1β, IL-6 and TNF-α was detected by RT-qPCR. Proteomics studies the signaling pathways that may be affected by PHI. Molecular docking technology was used to study the possible targets of PHI on NF-kB pathway. Western blot was performed to detect progressive changes in protein expression.Results: The research showed that PHI significantly inhibited the robust increase of IL-1β and PGE2, and lowered the transcriptional level of inflammatory genes including IL-6, IL-1β and PGE2 in LPS-stimulated RAW264.7 cells. Proteomics results indicated that PHI was involved in the regulation of multiple signaling pathways. Molecular docking results indicated that PHI has an affinity for most proteins in NF-kB pathway. Western blot analysis showed that PHI inhibited LPS-induced NF-κB pathway activation. Conclusion: PHI inhibits the activation of NF-κB pathway, thereby inhibiting the expression of related inflammatory genes and the release of cytokines, thus showing remarkable anti-inflammatory effect.

scholarly journals Atazanavir is a competitive inhibitor of SARS-CoV-2 Mpro, impairing variants replication in vitro and in vivo

2021 ◽  
Author(s):  
Otavio Augusto Chaves ◽  
Carolina Q. Sacramento ◽  
Andre Costa Ferreira ◽  
Mayara Mattos ◽  
Natalia Fintelman-Rodrigues ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Competitive Inhibition ◽  
Competitive Inhibitor ◽  
Positive Control ◽  
Lethal Challenge ◽  
Angiotensin Converting Enzyme 2 ◽  
Main Protease ◽  
Docking Calculations

Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19), however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based, and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison's inhibitory constant (Ki) 1.5-fold higher than boceprevir (GC376, a positive control). ATV was a competitive inhibition, increasing the Mpro's Michaelis-Menten (Km) more than 6-fold. Cell-based assays indicated that SARS-CoV-2 gamma is more susceptible to ATV than its predecessor strain B.1. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the Mpro/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.

scholarly journals Molecular Docking and Virtual Screening based prediction of drugs for COVID-19

2020 ◽  
Vol 23 ◽  
Author(s):  
Sekhar Talluri
Keyword(s):  
Clinical Trials ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Genomic Sequence ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
X Ray Diffraction ◽  
Main Protease ◽  
Docking Calculations ◽  
Approved Drugs

Aims: To predict potential drugs for COVID-19 by using molecular docking for virtual screening of drugs approved for other clinical applications. <p> Background: SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by WHO due to high mortality, high basic reproduction number and lack of clinically approved drugs and vaccines for COVID-19. The genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three dimensional structure of the Main protease are available. <p> </p> Objective: To identify potential drugs that can be repurposed for treatment of COVID-19 by using molecular docking based virtual screening of all approved drugs. <p> </p> Methods: List of drugs approved for clinical use was obtained from SuperDRUG2 database. The structure of the target in the apo form, as well as structures of several target-ligand complexes, were obtained from RCSB PDB. The structure of SARS-CoV-2 Mpro determined from X-ray diffraction data was used as the target. Data regarding drugs in clinical trials for COVID-19 was obtained from clinicaltrials.org. Input for molecular docking based virtual screening was prepared by using Obabel and customized python, bash and awk scripts. Molecular docking calculations were carried out with Vina and SMINA, and the docked conformations were analyzed and visualized with PLIP, Pymol and Rasmol. <p> </p> Results: Among the drugs that are being tested in clinical trials for COVID-19, Danoprevir and Darunavir have the highest binding affinity for the target main protease of SARS-CoV-2. Saquinavir and Beclabuvir were identified as the best novel candidates for COVID-19 therapy by using Virtual Screening of drugs approved for other clinical indications. <p> </p> Conclusion: Protease inhibitors approved for treatment of other viral diseases have the potential to be repurposed for treatment of COVID-19. </p>

scholarly journals Anti-inflammatory activities of Sigesbeckia glabrescens Makino: combined in vitro and in silico investigations

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Zhangfeng Zhong ◽  
Qianru Zhang ◽  
Hongxun Tao ◽  
Wei Sang ◽  
Liao Cui ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Inflammatory Diseases ◽  
Chemical Constituents ◽  
Western Blots ◽  
Novel Approach ◽  
Inflammatory Mechanism ◽  
Mapk Signalling ◽  
Anti Inflammatory

Abstract Background Sigesbeckia glabrescens Makino (SG) is one of the important plant origins of Sigesbeckiae herba and has been widely used for the treatment of chronic inflammatory diseases in China. However, the underlying anti-inflammatory mechanism of SG is rarely investigated and reported. There are more than 40 kinds of chemical constituents in SG, but the action of the bioactive compounds of SG is still unclear. Therefore, we aimed to systemically investigate the mechanisms behind the anti-inflammatory properties of SG by combining in vitro and in silico investigations. Methods Cytotoxicity was measured using the 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Nitric oxide (NO) release was detected using the Griess assay. The secretion of pro-inflammatory cytokines and the expression of relevant proteins were assessed using ELISA kits and Western blots, respectively. Molecular docking was performed and scored using AutoDock via a comparison with the molecular docking of N-acetyl-d-glucosamine (NAG). Results In lipopolysaccharides (LPS)-stimulated macrophages, SG significantly inhibited NO, MCP-1, and IL-6 secretion; iNOS expression; and NF-κB activation but did not significantly affect MAPK signalling (p38, ERK, and JNK). Moreover, the results from the molecular docking prediction suggested that over 10 compounds in SG could likely target TLR4, p105, and p65. Conclusions These findings suggest that the anti-inflammatory effects of SG are highly related to the inactivation of NF-κB. Moreover, this study provides a novel approach to investigate the effects of herbal medicine using combined in vitro and in silico investigations.

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